Medicinal compositions for treatment of atrial fibrillation

ABSTRACT

The present invention relates to a medical composition for atrial fibrillation treatment, comprising a compound represented by the following formula [I]: 
     Formula [I]                   
     [wherein R 1  represents a hydrogen atom or lower alkoxy group; R 2  represents a hydrogen atom, lower alkoxy group or phenyl group (wherein the phenyl group may be substituted with 1 to 3 substituents selected from a group consisting of a hydroxides group and a lower alkoxy group),                    
     (wherein R 3  represents an acyl group); X represents —CO— or —CH 2 —, and n represents an integer of 1 or 2.] The present invention also relates to a method of treating atrial fibrillation using said compound, and to the use of said compound for producing a medicine for atrial fibrillation treatment or salts thereof or prodrugs thereof.

TECHNICAL FIELD

The present invention relates to a medical composition for atrialfibrillation treatment to mammals including human, which includes1,4-benzothiazepine derivatives. The present invention also relates to amethod of treating atrial fibrillation using such derivatives and to theuse of such derivatives for producing a medicine for atrial fibrillationtreatment.

BACKGROUND ART

While atrial fibrillation is not a lethal arrhythmia, its morbidity issignificantly high as 0.4 to 0.9% of the entire population,. and itsfrequency increases with aging. Such arrhythmia raises the risk rate ofcerebral infarction up to about five times, and simultaneouslydeteriorates exercise capacity. Thus, the atrial fibrillation has beenfurther emphasized as critical arrhythmia in conjunction withprogressive increasing in elderly population.

Atrial fibrillation may be defined as a state when disordered excitationor activation is occurring frequently and irregularly in a small part ofthe atrium without harmonious excitation and construction of the entireatrium. Correspondingly, an electrocardiogram indicates waves having abaseline which fluctuates minutely and continuously (so-called “fwave”). This abnormal atrial activation is irregularly conducted to theventricle through the atrio ventricular node. This causes completelyirregular contractions in the ventricle, and absolute arrhythmia appearsin pulsation. The arrhythmia includes transient (paroxysmal) arrhythmiawhich frequently occurs and perpetual arrhythmia.

As to their generation mechanism, the “Reentry” theory and “EctopicImpulse Generation” theory have been suggested. However, it has not beenachieved to explain all of the mechanism based on a single theory.

The term “Reentry” means a phenomenon such that once an occurredexcitation is conducted through other cardiac regions and then excitesthe former region again. Once action potential is generated in a singlemyocardial cell, the resulting stimulation causes depolarization inadjacent cells, and this stimulation is conducted from one cell toanother. Generally, myocardial cells are adapted not to be immediatelyre-excited due to its long refractory period after the action potentialhas been generated in one myocardial cell, so that the Reentry is notinherently worked out. Thus, it is required to satisfy the followingfour conditions to realize the Reentry;

(1) Presence of unidirectional block,

(2) Delay of conduction,

(3) Shortening of refractory period,

(4) Presence of Reentry path.

In these conditions, the presence of unidirectional block is mostimportant. That is, if the conduction is bidirectional or bothdirections of the conduction are blocked, the Reentry cannot berealized. Excessive conduction velocity disenables the re-excitationbecause the refractory period is not passed over even if the excitationreturns to the former region. Thus, the conduction is necessary to betardy and slow. Further, shortened refractory period is advantageous tofacilitate the establishment of the Reentry.

Diseases caused by atrial fibrillation include mitral valve pathology,ischemic heart disease, hypertension, various cardiomyopathies,constrictive pericarditis, and Basedow's disease. However, it is oftenthe case that underlying diseases are not clear.

As to therapeutic agents for atrial fibrillation, Japanese PatentLaid-Open Publication No. Sho 49-000265 describes benzothiazolederivatives represented by the following formula;

Japanese Patent Laid-Open Publication No. Sho 63-255278 (European PatentNo.285323, U.S. Pat. No. 4,822,793) describes benzazepine derivativesrepresented by the following formula;

Japanese Patent Laid-Open Publication No. Hei 04-234386 (European PatentNo. 467325, U.S. Pat. No. 5,082,847) describes carbostyril derivativesrepresented by the following formula;

and Japanese Patent Laid-Open Publication No. Hei 09-169743 describeshexahydro-1H-1,4-diazepine derivatives represented by the followingformula.

While another publications other than these documents describe variouscompounds, they do not describe 1,4-benzothiazepine derivatives as inthe present invention.

On the other hand, Japanese Patent Laid-Open Publication No. Hei04-230681 (International Publication No. WO92/12148, European Patent No.565721, U.S. Pat. No. 5,416,066) describes 1,4-benzothiazepinederivatives or pharmaceutically acceptable salts represented by thefollowing formulas and a manufacturing method thereof.

[wherein R represents a hydrogen atom or lower alkoxy group having 1 to3 carbon atoms; R¹ represents a hydrogen atom, lower alkoxy group having1 to 3 carbon atoms, or substituted phenyl group (wherein thesubstituent is a hydroxyl group or lower alkoxy group having 1 to 3carbon atoms),

(wherein R² represents an acyl group); X represents an oxygen atom orH2; n represents an integer of 1 or 2; and Ph represents a phenylgroup.]

According to the Japanese Patent Laid-Open Publication No. Hei04-230681, it is described that there are two patterns of necrosis[Static cell death (SD) and Kinetic cell death (KD)] in myocardium ofcardiac infarction patients and the major cell death in human cardiacinfarction is classified into the KD. It is also described that theinvented compounds have an excellent KD suppression effect. However, inthis document, no description is included which suggests a certainapplication as therapeutic agents for atrial fibrillation treatment.

DISCLOSURE OF INVENTION

It is an object of the present invention to provide a therapeutic agentfor atrial fibrillation treatment to mammals including human.

It is another object of the present invention to provide a method oftreating atrial fibrillation to mammals including human.

As a result of a continuous research for achieving the above objects,the inventors have found out that a compound represented by thefollowing formula [I] is amazingly excellent in anti-atrial fibrillationeffects, and have completed the present invention.

The present invention is directed to a therapeutic agent for atrialfibrillation treatment, comprising a compound represented by thefollowing formula [I] as an active component. The details will be shownas the following (1) to (7).

(1) A medical composition for atrial fibrillation treatment comprising acompound represented by the formula [I]:

Formula [I]

[wherein R¹ represents a hydrogen atom or lower alkoxy group; R²represents a hydrogen atom, lower alkoxy group or phenyl group (thephenyl group may be substituted with 1 to 3 substituents selected from agroup consisting of a hydroxides group and a lower alkoxy group),

(wherein R³ represents an acyl group); X represents —CO— or —CH2—, and nrepresents an integer of 1 or 2.] or salts thereof or prodrugs thereof;and a pharmaceutically acceptable carrier.

(2) A medical composition as defined in the above (1), wherein saidcompound is consisting of4-[3-(4-benzylpiperidine-1-yl)propionyl]-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine,salts thereof or prodrugs thereof.

(3) A method of treating atrial fibrillation comprising administering aneffective amount of a compound represented by the above formula [I],salts thereof or prodrugs thereof.

(4) A method as defined in the above (3), wherein said compound isconsisting of4-[3-(4-benzylpiperidine-1-yl)propionyl]-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine,salts thereof or prodrugs thereof.

(5) The use of a compound represented by the above formula. [I], saltsthereof or prodrugs thereof, for producing a medicine for atrialfibrillation treatment.

(6) The use as defined in the above (5), wherein said compound isconsisting of4-[3-(4-benzylpiperidine-1-yl)propionyl]-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine,salts thereof or prodrugs thereof.

(7) A commercial package comprising a medical composition as defined inthe above (1) or (2) together with the printed matter relating to saidmedical composition, said instruction describing that said medicalcomposition is useable or to be used for atrial fibrillation treatment.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a graph representing an effect such that a compound 1 reducesa duration of an atrial fibrillation induced by means of electricalstimulation in example 3.

FIG. 2 is a graph representing an effect such that a compound 1 expandsa time interval of an atrial fibrillation induced by means of electricstimulation in example 3.

DETAILED DESCRIPTION OF THE INVENTION

The terms used in this specification are defined as follows.

The “lower alkoxy group” means straight-chained or branched alkoxygroups having 1 to 6 carbon atoms. For example, the lower alkoxy groupincludes a methoxy group, ethoxy group, propoxy group, isopropoxy group,butoxy group, tert-butoxy group, pentyloxy group, tert-pentyloxy groupor hexyloxy group, preferably, the methoxy group, ethoxy group, propoxygroup or isopropoxy group, which has 1 to 3 carbon-atoms, morepreferably, the methoxy group.

The “acyl group” includes a formyl group having 1 carbon atom; alkanoylgroup having 2 to 6 carbon atoms, such as acetyl group, propionyl group,butyryl group, or pivaloyl group; or aryl group, such as benzoyl group,which may have 1 to 3 substituents on a aryl group. Preferably, the acylgroup is the formyl group, acetyl groups, pivaloyl groups or benzoylgroups.

The “salts” of the compound shown in the formula [I] arepharmaceutically acceptable salts, and includes, but not limited to, aninorganic acid adduct salt, such as hydrochloride, hydrobromide,sulfate, phosphate, or nitrate; organic acid adduct salt, such asacetate, propionate, succinate, glycolate, lactate, malate, oxalate,tartrate, citrate, maleate, fumarate, methanesulfonate,benzenesulfonate, p-toluenesulfonate or ascorbate; and amino acid adductsalts, such as aspartate or glutamate. The salts may be hydrousmaterials or hydrates.

The “prodrugs” of the compound shown in the formula [I] is derivativesof the compound of the present invention, which have chemically ormetabolically decomposable groups and exhibit pharmaceutical activitiesthrough hydrolysis, solvolysis or decomposition under physiologicalconditions.

In the compound shown in the formula [I] according to the presentinvention, preferably, the R¹ is a lower alkoxy group having 1 to 3carbon atoms, and more preferably, a methoxy group. Preferably, the R²is a lower alkoxy group having 1 to 3 carbon atoms or a hydrogen atom,and more preferably, a hydrogen atom. Preferably, the X is —CO—.Preferably, the n is 2.

It is preferable that the compound represented by the formula [I] or thesalts thereof is used as the active component of the medicines ormedical composition for atrial fibrillation treatment.

The compound represented by the formula [I] according to the presentinvention may be produced based on the method described in JapanesePatent Laid-Open Publication No. Hei 04-230681 (InternationalPublication No. WO092/12148, European Patent No. 565721, U.S. Pat. No.5,416,066).

The compound represented by the formula [I] according to the presentinvention has an excellent anti-atrial fibrillation effect. When thecompound of the present invention is used for atrial fibrillationtreatment, it is typically administered generally or locally in oral orparenteral manner.

While the administered amount of the compound is varied depending onage, body weight, symptom, effectiveness, treatment time and others, thecompound is typically administered in the range from 0.01 mg to 1 g peradult patient in oral or parenteral manner, once or several times a day.

The method of atrial fibrillation treatment of the present inventioncomprises administrating the effective amount of the compoundrepresented by the formula [I], the salts thereof or the prodrugsthereof to mammals, preferably to human, necessary to be treated.

The compound represented by the formula [I] according to the presentinvention, the salts thereof or the prodrugs thereof may be administeredin forms of a medical composition with a pharmaceutically acceptablecarrier.

In case that the compound of the present invention is formed in a solidcomposition for oral administration, any suitable form, such as tablet,pill, powder or granule may be applied. In such a solid composition, oneor more active materials are mixed with at least one inactive diluent,dispersant or absorbent, such as lactose, mannitol, glucose,hydroxypropyl cellulose, microcrystalline cellulose, starch,polyvinylpyrrolidone, magnesium alminate metasilicate or silicic acidanhydride powder. Any suitable additives other than diluents may bemixed with the composition in accordance with ordinary manners.

In case that the compound is prepared as a tablet or pill, the compoundmay be coated with a film formed of a material soluble in stomach orintestine, such as white sugar, gelatin, hydroxypropyl cellulose orhydroxymethyl cellulose phthalate, and may be coated with two or morelayers. Further, the compound may be capsulated in a material, such asgelatin or ethylcellulose.

In case that the compound is formed in a liquid composition for oraladministration, any pharmaceutically acceptable form, such as anemulsion, solvent, suspension, syrup or elixir may be applied. Theapplied diluent may include purified water, ethanol, plant oils oremulsifier and so on. In addition to diluents, this composition may bemixed with an auxiliary agent, such as a wetting agent, suspension,edulcorant, flavors, aromatic, or preservative.

In case that the compound is prepared as injection for parenteraladministration, a sterile aqueous or non-aqueous solvent, solubilizer,suspension, or emulsifier is used. The aqueous solvent, solubilizer orsuspension may, for example, include a water for injection, distilledwater for injection, physiological salt solution, cyclodextorin andderivatives thereof, organic amine, such as triethanolamine,diethanolamine, monoethanolamine, or triethylamine, or inorganicalkaline solution.

In case of preparing as water-soluble solution, propylene glycol,polyethylene glycol, plant oils such as olive oil, or alcohol such asethanol or the like may be applied. For solubilizer, surfactant such aspolyoxyethylene hardened castor oil or sugar fatty acid esters (to formmixed micelle), or lecithin or water added lecithin (to form liposome)may be applied. Further, the compound may be prepared as an emulsionformed of a non-aqueous solvent such as plant oils, lecithin, andpolyoxyethylene hardened castor oil orpolyoxyethylene-polyoxypropylene-glycol.

Another composition for parenteral administration includes a linimentsuch as external solution or ointment, suppositories, or pessary, whichincludes one or more active materials and are prescribed through awell-known method.

EXAMPLE

Now, examples of preparation of a compound of the present invention willbe described.

For a compound as preparation,4-[3-(4-benzylpiperidine-1-yl)propionyl]-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine(hereinafter, referred to as Compound 1) was used.

Example 1

Preparation for Injection

Compound 1 2˜40 mg

D-sorbitol 1000 mg

citric acid 10 mg

sodium hydroxide proper quantity

Water for injection is added to these materials, to thereby prepare 20.0ml of solution.

D-sorbitol and citric acid were dissolved in a sufficient amount ofinjection water. Compound 1 was dissolved in the resulting solution, andthe solution was adjusted in pH of 3.2 to 3.3 by adding sodiumhydroxide.

While stirring, the remaining injection water was added to the solution.The resultant solution was filtered and put into 20.0-ml ampoule, andsealed. Subsequently, the content of the ampoule was subjected toautoclave sterilization.

A pharmacological test of the inventive compound will be specificallydescribed. Compound 1 was used as a subject compound.

Example 2

A beagle was used in the experimental test. Its right atrial. muscle wassurgically extracted, and a sample was fixed with pins within anexperimental vessel which is perfused with Tyrode liquid (10 ml/min).Using an electrical stimulator, the atrial muscle was stimulated by avoltage two times greater than that of generating an active potential,and rectangular waves having pulse. width of 2 msec in a frequency of 2Hz, and the generated active potential was measured by a glassmicroelectrode inserted into the cells. Compound 1 was added into theexperimental vessel with condensations of 0.3 μM and 1 μM. At 90 minutesbefore and after adding the compound, the sample was excited withvarious excitation frequencies, and each active potential was recordedto. determine the duration (90% recovery time; APD90). The result isshown in Table 1.

TABLE 1 excita- 0.3 μM 1 μM tion duration duration fre- before changebefore change quency addition (ms after addition (ms after (Hz) ec)addition (%) ec) addition (%) 3.33 124.3 ± 6.08  111.5 ± 10.52 137.4 ±9.52  124.7 ± 9.40 2  160.9 ± 13.62 113.0 ± 1.48 173.0 ± 9.17  118.1 ±2.88 1 205.9 ± 9.95 110.1 ± 2.75 209.0 ± 18.40 111.3 ± 5.34 0.67 214.3 ±6.96 106.0 ± 2.01 214.3 ± 20.31 112.9 ± 6.47

From the result of the table 1, it was proved that Compound 1 (0.3 μMand 1 μM) provided a longer duration of the active potential of theatrial muscle. This result shows that Compound 1 has an anti-atrialfibrillation effect.

Example 3

In the experimental test, a hybrid of a labrador and beagle was used. Anelectrode for electrical excitation was embedded in the right atrium.From a week after the operation, the right atrium was subjected to acontinuous pacing at an excitation frequency of 400 or 600 bpm by anexternal pacemaker. Further, for 31 day, the right atrium was subjectedto a pacing giving a burst excitation (10 mA,50 Hz,1 sec) 5 days a weekand several hours a day. Compound 1 was continuously injected intoforearm vein (0.3mg/kg/min×2 min+0.03 mg/kg/min). At 20 minutes beforeand after administrating, the excitation current (50 Hz, 1 sec) wasincreased from 3 mA to 10 mA in increments of 0.5 mA to determine eachatrial fibrillation threshold (AFT). Then, the atrial fibrillationduration (AF duration) and the interval (FF interval) of atrialfibrillation waves, which were generated by the excitation current of 10mA, were measured. The result is shown in FIG. 1 and 2. In FIG. 1, themean value of the AF duration before administration was 35.1±9.0 sec,and the mean value after administration was 12.1±1.9 sec. In FIG. 2, themean value of the FF interval before administration was 51.3±1.7 msec,and the mean value after administration was 61.7±1.8 msec.

By virtue of the administration of Compound 1, the AFT was increasedfrom 7 mA to 10 mA. In addition, the AF duration was reduced down toabout one third as shown in FIG. 1, and the FF interval is additionallyextended about 20% as shown in FIG. 2. From this result, it has beenproved that Compound 1 had an anti-atrial fibrillation effect.

INDUSTRIAL APPLICABILITY

As is apparent from the above examples, the compound represented by theformula [I] according to the present invention has an excellentanti-atrial fibrillation effect to mammals including human. Thus, it isexpected to provide a significantly effective therapeutic agent foratrial fibrillation.

This application is based on Japanese patent application No. Hei10-373332 filed in Japan, and all of its contents are included in thisapplication.

What is claimed is:
 1. A method of treating atrial fibrillationcomprising administering an effective amount of a compound representedby the following formula [I]:

[wherein R¹ represents a hydrogen atom or lower alkoxy group; R²represents a hydrogen atom, lower alkoxy group or phenyl group (whereinthe phenyl group may be substituted with 1 to 3 substitutents selectedfrom a group consisting of a hydroxides group and a lower alkoxy group),

(wherein R³ represents an acyl group); X represents —CO— or —CH₂—, and nrepresents an integer of 1 or 2 or salts thereof or prodrugs thereof. 2.A method as defined in claim 1 wherein said compound is consisting of4-[3-(4-benzylpiperidine-1-yl)propionyl]-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine,salts thereof or prodrugs thereof.
 3. The use of a compound representedby the following formula [I]:

[wherein R¹ represents a hydrogen atom or lower alkoxy group; R²represents a hydrogen atom, lower alkoxy group or phenyl group (whereinthe phenyl group may be substituted with 1 to 3 substituents selectedfrom a group consisting of a hydroxides group and a lower alkoxy group),

(wherein R³ represents an acyl group); X represents —CO— or —CH₂—, and nrepresents an integer of 1 or 2 or salts thereof, for producing amedicine for atrial fibrillation treatment.